Regulation of neurotrophins

ABSTRACT

Disclosed are methods for regulating neurotrophin levels within a human body. The invention utilizes an implantable signal generator to deliver stimulation to neural tissue elements. Alternatively, an implantable pump may be utilized to delivery one or more drugs. The implanted device delivers treatment therapy to the neural tissue to thereby alter the level of neurotrophic factors such as BDNF expressed by the influenced neural tissue. A sensor may be used to detect various symptoms of a nervous system disorder. A microprocessor algorithm may then analyze the output from the sensor to regulate the treatment therapy delivered to the body. The invention describes a novel method to regulate the intrinsic levels of neurotrophins and may be used to treat patients with neurological and cognitive disorders.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/303,619 (Attorney Docket No. 41551-707.201), filed Dec. 16, 2005,which claims the benefit of Provisional Application No. 60/671,723(Attorney Docket No. 41551-707.101), filed Apr. 15, 2005, the fulldisclosures of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to techniques for regulating the level ofone or more neurotrophic factors within a human body by way ofelectrical stimulation and/or drug infusion.

It has generally been believed that loss of neurons in the adult humanbrain—as it occurs in aging humans and in neurological disorders—is anirreversible process. Many major diseases of the human brain involvedeficiencies of select neuronal populations. The inability by the adulthuman brain to generate replacement cells is thought to be a leadingcause for the irreversible and progressive nature of severalneurological diseases and is responsible for persistent and ongoingimpairment. In most regions of the human brain, the generation ofneurons is generally confined to a discrete developmental period. Afterthis developmental period, it believed that further generation of braincells occurs only to a limited extent and is restricted to specificareas in the living human brain.

Neurotrophins play an important role in the development, regeneration,synaptogenesis and connectivity of neurons in mammals. Neurons such asbasal forebrain cholinergic neurons, motor neurons and sensory neuronsof the central nervous system—remain responsive to neurotrophic factorseven in adult humans. The presence of neurotrophic factors may evenfacilitate the regeneration of neurons and the repair of neural circuitsafter loss or damage. Work with cell cultures and animal models hasshown that neurotrophins prevent neuronal death, induce neural sproutingand enhance neural recovery and repair. In addition to neurogenesis,neurotrophins are known to have a variety of beneficial effects onneurons including, neuroprotection, rescue from toxicity or injury, andinduction of synaptogenesis.

Moreover, while no evidence yet exists that a lack of neurotrophinsunderlies the etiology of any neurodegenerative disease, these studieshave spurred on hopes that neurotrophins might be usefulsymptomatic-therapeutic agents. It is believed that neurotrophins may beuseful for the treatment of neurodegenerative conditions such asAlzheimer's Disease (AD), Parkinson's Disease (PD), amyotrophic lateralsclerosis (ALS), peripheral sensory neuropathies and spinal cordinjuries. In addition, neurotrophins may act on neurons affected byother neurological and psychiatric pathologies including ischemia,epilepsy, depression and eating disorders. For example, Brain-DerivedNeurotrophic Factor (BDNF) is known to modulate synaptic function aswell as to promote neuronal growth in the adult brain. The reduction inBDNF expression for example has been implicated to be important instress and in depression.

In the prior art, attempts have been made to treat neurodegenerativeconditions by infusing neurotrophins into to the patient. For example,U.S. Pat. No. 6,815,431 discloses methods for intraparenchymal deliveryof neurotrophins to defective, diseased or damaged cells in themammalian brain using a lentiviral expression vector. However, the priorfails to disclose any techniques for regulating the human body's ownexpression of neurotrophic factors.

BRIEF SUMMARY OF THE INVENTION

An embodiment of the invention uses electrical stimulation of nerveelements of a human body to regulate the expression of neurotrophicfactors. The treatment is carried out by an implantable signal generatorand at least one implantable electrode having a proximal end coupled tothe signal generator and having a stimulation portion for electricallyaffecting nerve elements of the human body. In one embodiment, themethod regulates the expression of Brain-Derived Neurotrophic Factor(BDNF) in the brain to treat various neurodegenerative, neurological,psychiatric and cognitive disorders. Alternatively, the treatment may becarried out by an implantable pump and at least one catheter having aproximal end coupled to the pump and having a discharge portion forinfusing therapeutic dosages of the one or more drugs into apredetermined infusion site at or near nerve elements. By using theforegoing techniques, the nerve elements may be stimulated to increaseor decrease its production of neurotrophic factors. In other embodimentsof the invention, drug infusion may be used as treatment therapy insteadof or in addition to the electrical stimulation.

In another embodiment of the invention, a sensor is used in combinationwith the signal generator and stimulating electrodes to regulateexpression of neurotrphic factors. Control means responsive to thesensor may thereby regulate the signal generator and/or pump so that theneurological disorder is treated.

By using the foregoing techniques, neurodegenerative and cognitivedisorders can be controlled or treated through the regulation of theexpression of neurotrophic factors.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatic illustration of an electrode implanted in abrain according to a preferred embodiment and a signal generator coupledto the electrode.

FIGS. 2 and 2A are diagrammatic illustrations of a catheter implanted ina brain according to a preferred embodiment.

FIG. 3 is a schematic block diagram of a microprocessor and relatedcircuitry of an implantable medical device for use with the invention.

FIG. 4( a) is a diagram depicting the anterior thalamic nuclei complexand FIG. 4( b) is a diagram depicting the dentate gyrus.

DETAILED DESCRIPTION OF THE INVENTION

The invention discloses techniques for delivering treatment therapy tonerve elements of a human body to regulate the body's expression ofneurotrophic factors. In an embodiment, the regulation of Brain-DerivedNeurotrophic Factor (BDNF) in the brain may be performed to treatvarious neurodegenerative, neurological, psychiatric and cognitivedisorders and/or to treat locations of the body exhibiting neuronal lossor damage. However, it will be appreciated by those skilled in the artthat the present application covers regulation of any number ofneurotrophic factors and their receptors including, but not limited to,Artemin, CNTF, Erbs, EGF, FGFs, GDNF, GFRas, gp130, IGFs, Neuregulins,Neurturin, b-NGF, NT-3, NT-4, Neuropilins, PDGFs, Persephin, Ret, Trks,and VEGFs.

Moreover, depending on where it is desired to regulate neurotrophinexpression, any nerve area of the human body may be influenced includingthe brain (cortical areas and sub-cortical areas such as deep brainelements), the spinal cord or peripheral nerves. Accordingly, theinvention incorporates electrical stimulation and/or drug infusiontechniques to directly or indirectly influence tissue elements withinthe brain. One or more electrodes and/or catheters are implanted in thebrain so that the stimulation or infusion portions lie within or incommunication with predetermined portions of the brain. The electricalstimulation or drug therapy influences the predetermined brain elementsto achieve the desired result in the expression of neurotrophic factors.

These techniques of the present invention are suitable for use withinany implantable medical device. In a preferred embodiment, the presentinvention is implemented within an implantable neurostimulator system,however, those skilled in the art will appreciate that the presentinvention may be implemented generally within any implantable medicaldevice system including, but not limited to, implantable drug deliverysystems, implantable systems providing stimulation and drug delivery.

The present invention may be utilized to treat, for example, any numberof conditions that result from neuronal loss or damage including, butnot limited to, depression, epilepsy, post cranial irradiation, steroidinduced impairment, stress disorders, cognitive disorders, Alzheimer'sdisease, and other neurodegenerative diseases. Such otherneurodegenerative diseases include, for example, Amyotrophic lateralsclerosis (ALS), Huntingtons, Spinocerebellar ataxias (SCA's). Moreover,in certain applications, the present application may be desirable toreduce the level of neurotrophins in a body. For example, circumstanceswhere it may desirable to reduce levels of neurotrophins include incases of painful neuropathies to reduce neural sprouting and in cases ofepilepsy to reduce maladaptive sprouting and synaptogenesis.

As discussed, the targeted treatment site includes any nerve locationwithin the body, and in one embodiment includes the brain (the cortexand/or the sub-cortex). For cortex stimulation, a multi contact corticalbrain surface electrode (e.g., Medtronic Resume) may be utilized. Forsub-cortex stimulation, a deep brain electrode may be utilized. Thesub-cortex can include deep brain elements such as, for example, theanterior thalamic nuclei complex (FIG. 4( a), the dentate gyrus (FIG. 4(b)) the periventricular zone, the Papez circuit, and the cerebellum. ThePapez circuit is generally a neuronal circuit in the limbic system,consisting of the hippocampus, formix, mammillary body, anteriorthalamic nuclei, and cingulate gyrus. Stimulation or drug therapy alongthe Papez circuit may lead to expression of neurotrophic factors in thehippocampus. When the periventricular zone is influenced in accordancewith the present invention, new neurons may migrate to the striatum,cortex, or the substantia nigra, and brainstem and therefore lead toexpression of neurotrophic factors in such areas. The cerebellum isanother brain location where increased expression of neurotrophicfactors may be therapeutically desirable. In general, the foregoingtechniques may be used to regulate expression of neurotrophic factors byapplication of electrical stimulation or drug therapy in either thecerebellum or cerebellar afferent or efferents.

Thus, the site of stimulation or drug infusion may be chosen based onthe neural structures that are affected by neuronal loss and which oneswould benefit from the regulation of neurotrophincs. For example,targeting the hippocampal neuronal loss may utilized to treatdepression, epilepsy, post cranial irradiation, steroid inducedimpairment in neurogenesis, stress disorders, cognitive disorders andAlzheimer's disease. Targeting the cortical, striatal, substantia nigra,brainstem and cerebellar loss may be utilized to treat Huntington'sDisease, Alzheimers, multiple system atrophy, Parkinson's disease,post-irradiation disorders, paraneoplastic disorders and theSpinocerebellar ataxias. The techniques of the present invention mayalso be applicable to treat neuronal loss that occurs as a consequenceof congenital disorders, stroke, anoxia, hypoxia, hypoglycemia,metabolic disorders, head injury, drug and alcohol toxicity, nutritionaldeficiencies, auto-immune disorders, immune disorders, infectious andinflammatory processes.

Referring to FIG. 1, an implantable neurostimulator device 16 made inaccordance with the preferred embodiment may be implanted below the skinof a patient. A lead 522A is positioned to stimulate a specific site 525in a brain (B). Device 16 may take the form of a modified signalgenerator Model 7424 manufactured by Medtronic, Inc. under the trademarkItrel II which is incorporated by reference. Lead 522A may take the formof any of the leads sold with the Model 7424 such as Model 3387, forstimulating the brain, and is coupled to device 16 by a conventionalconductor 522. One or more external programmers (not shown) may beutilized to program and/or communicate bi-directionally with theimplanted device 16.

As shown, the distal end of lead 522A terminates in four stimulationelectrodes implanted into a portion of the brain by conventionalstereotactic surgical techniques. Each of the four electrodes isindividually connected to device 16 through lead 522A and conductor 522.Lead 522A is surgically implanted through a hole in the skull 123 andconductor 522 is implanted between the skull and the scalp 125 as shownin FIG. 1. Conductor 522 is joined to implanted device 16 in the mannershown. Referring to FIG. 2A, device 16 is implanted in a human body 120in the location shown. Body 120 includes arms 122 and 123.Alternatively, device 16 may be implanted in the abdomen. Conductor 522may be divided into twin leads 522A and 522B that are implanted into thebrain bilaterally as shown. Alternatively, lead 522B may be suppliedwith stimulating pulses from a separate conductor and signal generator.Leads 522A and 522B could be 1) two electrodes in two separate nucleithat potentiate each others effects or 2) nuclei with opposite effectswith the stimulation being used to fine tune the response throughopposing forces. It will be appreciated, however, that any number ofelectrodes may be implanted within the brain in accordance with theinvention. Additionally, one or more secondary electrodes may beimplanted so that a secondary stimulation portion lies in communicationwith another predetermined portion of a brain. Moreover, as will bediscussed below, one or more catheters, coupled to a pump, may beimplanted so that a secondary stimulation portion lies in communicationwith the tissue elements of the brain.

The device 16 may be operated to deliver stimulation to deep braintissue elements to thereby regulate expression of neurotrophic factorswithin the human brain. The particular stimulation delivered may beperformed by selecting amplitude, width and frequency of stimulation bythe electrode. The possible stimulations include between 2 Hertz and1000 Hertz for frequency, between 0.1 Volts and 10.0 Volts for pulseamplitude, and between 30 .mu.Seconds and 450 .mu.Seconds for pulsewidth. The system may be utilized in monopolar, bipolar, or multipolarconfigurations, in an either continuous or cyclical mode, and in eitheran open loop or closed loop mode. In one embodiment, the applicant ofthe present application has shown through experimentation that DeepBrain Stimulation (DBS) in a rodent model increased the expression ofBDNF. The applicant used a Western Blot where the levels of BDNF proteinwere measured (using a BDNF specific antibody) in the hippocampus of arat receiving DBS in the anterior thalamus. Stimulation at highfrequency using the above parameters caused a large increase in thelevels of BDNF protein. This increase was specific to BDNF because thelevel of other proteins, such as the intracellular general metabolicprotein glyceraldehyde phosphate dehydrogenase, was unaffected by DBS.

Referring to FIG. 2, in another embodiment, the system or device of thepresent invention may utilize drug delivery as the form of treatmenttherapy. A pump 10 may be implanted below the skin of a patient. Thepump 10 has a port 14 into which a hypodermic needle can be insertedthrough the skin to inject a quantity of a liquid agent, such as amedication or drug. The liquid agent is delivered from pump 10 through acatheter port 20 into a catheter 422. Catheter 422 is positioned todeliver the agent to specific infusion sites in a brain (B). Pump 10 maytake the form of any number of known implantable pumps including forexample that which is disclosed in U.S. Pat. No. 4,692,147.

Like electrical stimulation, drug delivery may be use to influence nervetissue to increase or decrease its production of neurotrophins. Anynumber of drugs may be administered including, but not limited to, ananesthetic, a GABA agonist, a GABA antagonist, a glutamate antagonist, aglutamate agonist, a degrading enzyme, a reuptake blocker, and adopamine antagonist. An activating chemical may be used and includes anychemical that causes an increase in the discharge rate of neurotrophinsfrom a region. An example (for projection neurons which receiveglutamatergic excitation and GABA inhibition) would be an agonist of thetransmitter substance glutamate (facilitating the excitation) or a GABAantagonist (blocking the inhibition). Conversely, a blocking chemicalmay be used and includes any chemical that inhibits the projectionneurons thereby causing a decrease in the discharge rate ofneurotrophins from a region. An example would be a glutamate antagonist(blocks excitatory input to the projection nerve cells) or a GABAagonist (enhances inhibition of the projection neurons) or a localanesthetic such as lidocaine and related compounds or an infusion ofions (for example Potassium, Calcium, Sodium, Chloride) or agents toalter ionic concentration or pH level. An example of an activatingchemical is a GABA antagonist such as bicuculline and an example of ablocking agent would be a GABA agonist such as baclofen.

The distal end of catheter 422 terminates in a cylindrical hollow tube422A having a distal end 425 implanted, by conventional stereotacticsurgical techniques, into a portion of the brain to affect tissue withinthe human brain. Tube 422A is surgically implanted through a hole in theskull and catheter 422 is implanted between the skull and the scalp asshown in FIG. 2. Catheter 422 is joined to pump 10 in the manner shown.Pump 10 is implanted in a human body in a subcutaneous pocket located inthe chest below the clavicle; Alternatively, pump 10 may be implanted inthe abdomen.

Catheter 422 may be divided into twin tubes 422A and 422B (not shown)that are implanted into the brain bilaterally. Alternatively, tube 422B(not shown) implanted on the other side of the brain may be suppliedwith drugs from a separate catheter and pump.

The pump 10 may be programmed to deliver drug according to a particulardosage and/or time interval. For example, the pump may delivery drugtherapy over a first period when the dose is higher to increaseexpression of neurotrophic factors followed by a longer period ofongoing delivery to maintain neurotrophin factor levels and secondarytrophic effects like axonal sprouting and synaptogenesis.

Alternatively, a combination of treatment therapies may be delivered toprovide influencing of various neuronal types. For example, it may bedesirable to concurrently influence, via drug and/or electricalstimulation, the neurons in the hippocampus and other nerve elements inthe human body to achieve an improved result. Such a device to utilizeboth forms of treatment therapy may be that which is disclosed, forexample, in U.S. Pat. No. 5,782,798. In addition to affecting the deepbrain, it may be desirable to affect concurrently other portions of thehuman body.

Referring to FIG. 3, the overall components of the implanted device 16are shown (similar components may also be found for pump 10). Thestimulus pulse frequency is controlled by programming a value to aprogrammable frequency generator 208 using bus 202. The programmablefrequency generator provides an interrupt signal to microprocessor 200through an interrupt line 210 when each stimulus pulse is to begenerated. The frequency generator may be implemented by model CDP1878sold by Harris Corporation. The amplitude for each stimulus pulse isprogrammed to a digital to analog converter 218 using bus 202. Theanalog output is conveyed through a conductor 220 to an output drivercircuit 224 to control stimulus amplitude.

Microprocessor 200 also programs a pulse width control module 214 usingbus 202. The pulse width control provides an enabling pulse of durationequal to the pulse width via a conductor 216. Pulses with the selectedcharacteristics are then delivered from device 16 through cable 522 andlead 522A to the desired regions of the brain.

At the time the stimulation device 16 is implanted, the clinicianprograms certain key parameters into the memory of the implanted devicevia telemetry. These parameters may be updated subsequently as needed.

The embodiments of the present invention shown above are open-loopsystems. The microcomputer algorithm programmed by the clinician setsthe stimulation parameters of signal generator 16. This algorithm maychange the parameter values over time but does so independent of anychanges in symptoms the patient may be experiencing. Alternatively, aclosed-loop system discussed below which incorporate a sensor 130 toprovide feedback could be used to provide enhanced results. Sensor 130can be used with a closed loop feedback system in order to automaticallydetermine the level of electrical stimulation and/or drug deliverynecessary to achieve the desired regulation of neurotrophic factors. Ina closed-loop embodiment, microprocessor 200 executes a controlalgorithm in order to provide stimulation with closed loop feedbackcontrol. Such an algorithm may analyze a sensed signal and deliver theelectrical of chemical treatment therapy based on the sensed signalfalling within or outside predetermined values or windows, for example,for BDNF and other neurotrophins (e.g., NGF, CNTF, FGF EGF, NT-3) andcorticosteroids.

The control algorithm may be operable on-line or in real time bydetecting an electophysiological or chemical signal or off line bymeasuring a predetermined clinical benefit. Alternatively, the therapycould be guided by the goal of maintaining the population ofneurotrophic factors at to a certain level. This could be assessed usingthe techniques described below.

For example, the sensor 130 may generate a sensor signal related to thelevel of a particular neurotrophic factor (using known techniques suchas microdialysis or brain probe). As another example, the sensor 130 maygenerate a sensor signal related to the extent of neuronal loss. In anembodiment, the extent of electrical activity or the levels of aneurochemical may be measured that are indicative of neuronal loss. Forexample magnetic resonance spectroscopy may be used to sense theN-acetylaspartate (NAA) to creatine (Cr) ratio (NAA/Cr) as an indicatorof neuronal loss. Alternatively, the neuronal loss may be estimated bymeasuring the volume of the neural structure of interest, which may beachieved by Magnetic Resonance Imaging vollumetry. Any other techniquesmay also be used to sense the extent of neuronal loss including, forexample, MR volumetry, DWI, magnetization transfer MR imaging, and 1HMRS and PET).

As another example, the sensing may provide an indication of a cognitiveor neurological disorder. U.S. Pat. No. 6,227,203 provides examples ofvarious types of sensors that may be used to detect a symptom or acondition of a cognitive disorder and responsively generate aneurological signal. In an embodiment, a neurochemical characteristic ofthe cognitive function may be sensed, additionally or alternatively. Forexample, sensing of local levels of neurotransmitters (glutamate, GABA,Aspartate), local pH or ion concentration, lactate levels, localcerebral blood flow, glucose utilization or oxygen extraction may alsobe used as the input component of a closed loop system. Thesemeasurements could be taken at rest or in response to a specific memoryor cognitive task or in response to a specific sensory or motorstimulus. In another embodiment, an electro-physiological characteristicof the cognitive function may be sensed, for example, the frequency andpattern of discharge of individual neurons or the amplitude of a localelectric field potential. The information contained within the neuronalfiring spike train, including spike amplitude, frequency of actionpotentials, signal to noise ratio, the spatial and temporal features andthe pattern of neuronal firing, oscillation behavior and inter-neuronalcorrelated activity could be used to deliver therapies on a contingencybasis in a closed loop system. Moreover, treatment therapy delivered maybe immediate or delayed, diurnal, constant or intermittent depending oncontingencies as defined by the closed loop system.

In one embodiment, the system may provide continuous closed-loopfeedback control. In another embodiment, the system may be switchablebetween open-loop and closed-loop by operator control.

Referring back to FIG. 3, the system may optionally utilize closed-loopfeedback control having an analog to digital converter 206 coupled tosensor 130. Output of the A-to-D converter 206 is connected tomicroprocessor 200 through peripheral bus 202 including address, dataand control lines. Microprocessor 200 processes sensor data in differentways depending on the type of transducer in use and regulates delivery,via a control algorithm, of electrical stimulation and/or drug deliverybased on the sensed signal. For example, when the signal on sensor 130exceeds a level programmed by the clinician and stored in a memory 204,increasing amounts of treatment therapy may be applied through an outputdriver 224. In the case of electrical stimulation, a parameter of thestimulation may be adjusted such as amplitude, pulse width and/orfrequency.

Thus, embodiments of REGULATION OF NEUROTROPHINS are disclosed. Oneskilled in the art will appreciate that the present invention can bepracticed with embodiments other than those disclosed. The disclosedembodiments are presented for purposes of illustration and notlimitation, and the present invention is limited only by the claims thatfollow.

What is claimed is:
 1. A method for regulating the level of one or moreneurotrophic factors in neural tissue of the cortex or sub-cortex totreat or alleviate a neurological disorder involving neuronal loss ordamage, the method comprising: stimulating tissue of a neural circuit ofthe limbic system selected from the group consisting of the hippocampus,the fornix, the mammillary body, the anterior thalamic nuclei, and thecingulate gyrus through an electrode to thereby increase or decrease thelevel of the one or more neurotrophic factors and treat or alleviate theneurological disorder.
 2. The method as in claim 1, further comprisingselecting amplitude, width and frequency of stimulation energy to bedelivered by the electrode.
 3. The method as in claim 1, whereinstimulating comprises operating a signal generator to pulse electricalenergy at a frequency between 2 Hertz and 1000 Hertz.
 4. The method asin claim 3, wherein the signal generator is operated to pulse at a pulseamplitude between 0.1 Volts to 10.0 Volts.
 5. The method as in claim 4,wherein the signal generator is operated to pulse at a pulse widthbetween 30 microseconds and 150 microseconds.
 6. The method as in claim3, wherein the signal generator is operated in a monopolarconfiguration.
 7. The method as in claim 3, wherein the signal generatoris operated in a bipolar configuration.
 8. The method as in claim 3,wherein the signal generate is operated in a multipolar configuration.9. The method as in claim 3, wherein the signal generator is operated ina continuous mode.
 10. The method as in claim 3, where the signalgenerator is operated in a cyclical mode.
 11. The method as in claim 1,further comprising selecting between an open loop and a closed loop modeof operation.
 12. The method as in claim 1, wherein stimulatingcomprises adjusting at least one parameter of the stimulation, theparameter being selected from the group consisting of amplitude, pulsewidth and frequency.
 13. The method as in claim 1, further comprising:implanting at least one secondary electrode so that a secondarystimulation portion lies in communication with a portion of the body;coupling the secondary electrode to the signal generator; and operatingthe signal generator to stimulate the portion of the body.
 14. Themethod as in claim 1, further comprising: implanting at least onecatheter so that a discharge portion lies in communication with a secondneural tissue of said body; coupling the catheter to a pump; andoperating the pump to deliver drug to the second neural tissue tothereby alter the level of neurotrophin generated by the second neuraltissue.